The field of the invention is diabetes.
Diabetes mellitus is a prevalent and degenerative disease characterized by insulin deficiency, which prevents normal regulation of blood glucose levels leading to hyperglycemia and ketoacidosis.
Insulin promotes glucose utilization, protein synthesis, formation and storage of neutral lipids, and the growth of some cell types. Insulin is produced by the .beta. cells within the islets of Langerhans of the pancreas.
Some individuals with diabetes are not dependent upon the administration of exogenous insulin, other individuals are completely dependent upon exogenously administered insulin. Insulin-dependence is related to the degree of destruction of the .beta. islet cells. Diabetic patients that are not insulin-dependent can be diagnosed as having diabetes if they exhibit some of the symptoms of the disease, e.g., hyperglycemia, and have antibodies to insulin or islet cells, or both. Such patients may progress to full-blown insulin-dependent diabetes mellitus if they are not treated.
Insulin-dependent diabetes mellitus (IDDM) is a T cell dependent autoimmune disease. Activated T cells selectively target insulin producing beta cells and mediate their destruction. In the most severe form of diabetes, the autoimmune reaction causes complete destruction of .beta. cells, resulting in an absolute lack of insulin production in the individual.
The importance of T cells in human diabetogenic autoimmunity is emphasized by the ability of cyclosporine A to cause remission in new onset IDDM (Stiller et al., 1984, Science 223:1362). However, cyclosporin A-induced remissions have not been proven to be permanent, and the chronically administered high doses of cyclosporin A required to maintain a remission are associated with nephrotoxicity. Thus, cyclosporin A is an unlikely candidate for general clinical use (Drash et al., 1990, in Pediatric Clinics of North America: Current Issues in Pediatric and Adolescent Endocrinology 37:6).
Studies in the non-obese diabetic mouse (NOD) indicate that the disease in mice is similar to IDDM in humans (Makino et al., 1980, Exp. Anim. 29:1). Anti-T cell monoclonal antibodies (anti-Thy 1.2 or anti-CD4) prevent disease in NOD mice (Harada and Makino, 1986, Exp. Anim. 35:539; Shizura et al., 1988, Science 250:659) and anti-CD25 has been shown to prevent insulitis in NOD mice (Kelley et al., 1988, J. Immunol. 140:59). However, the action of anti-CD25 antibody was subsequently shown to be blocked by anti-idiotypic antibodies which had been generated in NOD mice (Pankewycz et al., 1988, J. Autoimmunity 1:119). T cell clones obtained from the islets of prediabetic mice with insulitis precipitate diabetes when transferred into prediabetic NOD mice (Pankewycz et al., 1991, Eur. J. Immunol. 21:873; Haskins et al., 1989, Proc. Natl. Acad. Sci. 86:8000).